Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by production of autoantibodies against nucleic acids, most prominently against double-stranded DNA (dsDNA). Defective clearance of DNA from apoptotic cells by DNA-degrading enzymes (DNases) has been implicated into the pathogenesis of SLE. We have characterized mice with targeted deletion of one such DNase, and observed that they develop prominent anti-dsDNA reactivity and other SLE manifestations. We therefore hypothesize that this mouse strain represents a robust monogenic model of SLE. We propose to validate this model and gain insight into the mechanism of the disease, using two Specific Aims. In Aim 1, we will characterize the kinetics and features of SLE development, as well as the role of innate DNA-sensing pathways. In Aim 2, we will test the cellular basis of the disease, particularly the role of dendritic cells in the breach of tolerance to self-DNA. Collectively, thes studies should establish a novel monogenic animal model that would be particularly suitable for genetic dissection of experimental SLE. In addition, they would validate a novel molecular culprit in the pathogenesis of SLE and characterize its role in immune tolerance to nucleic acids.